dc.contributor.author | Beites, T | |
dc.contributor.author | O'Brien, K | |
dc.contributor.author | Tiwari, D | |
dc.contributor.author | Engelhart, CA | |
dc.contributor.author | Walters, S | |
dc.contributor.author | Andrews, J | |
dc.contributor.author | Yang, H-J | |
dc.contributor.author | Sutphen, ML | |
dc.contributor.author | Weiner, DM | |
dc.contributor.author | Dayao, EK | |
dc.contributor.author | Zimmerman, M | |
dc.contributor.author | Prideaux, B | |
dc.contributor.author | Desai, PV | |
dc.contributor.author | Masquelin, T | |
dc.contributor.author | Via, LE | |
dc.contributor.author | Dartois, V | |
dc.contributor.author | Boshoff, HI | |
dc.contributor.author | Barry, CE | |
dc.contributor.author | Ehrt, S | |
dc.contributor.author | Schnappinger, D | |
dc.date.accessioned | 2020-12-09T10:37:23Z | |
dc.date.available | 2019-10-09 | |
dc.date.available | 2020-12-09T10:37:23Z | |
dc.date.issued | 2019-10-31 | |
dc.identifier.citation | Beites, T., O’Brien, K., Tiwari, D. et al. Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development. Nat Commun 10, 4970 (2019). https://doi.org/10.1038/s41467-019-12956-2 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/69162 | |
dc.description.abstract | The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice. Moreover, treatment of Mtb-infected marmosets with a cytochrome bc1-aa3 oxidase inhibitor controls disease progression and reduces lesion-associated inflammation, but most lesions become cavitary. Deletion of both NDH-2 encoding genes (Δndh-2 mutant) reveals that the essentiality of NDH-2 as shown in standard growth media is due to the presence of fatty acids. The Δndh-2 mutant is only mildly attenuated in mice and not differently susceptible to clofazimine, a drug in clinical use proposed to engage NDH-2. These results demonstrate the intrinsic plasticity of Mtb's respiratory chain, and highlight the challenges associated with targeting the pathogen's respiratory enzymes for tuberculosis drug development. | en_US |
dc.language | eng | |
dc.publisher | Nature Research | |
dc.relation.ispartof | Nature Communications | |
dc.rights | Creative Commons Attribution 4.0 International License | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Adaptation, Physiological | en_US |
dc.subject | Animals | en_US |
dc.subject | Antitubercular Agents | en_US |
dc.subject | Callithrix | en_US |
dc.subject | Drug Development | en_US |
dc.subject | Electron Transport | en_US |
dc.subject | Electron Transport Complex III | en_US |
dc.subject | Electron Transport Complex IV | en_US |
dc.subject | Gene Knockdown Techniques | en_US |
dc.subject | Imidazoles | en_US |
dc.subject | In Vitro Techniques | en_US |
dc.subject | Lung | en_US |
dc.subject | Mice | en_US |
dc.subject | Mycobacterium tuberculosis | en_US |
dc.subject | NADH Dehydrogenase | en_US |
dc.subject | Piperidines | en_US |
dc.subject | Pyridines | en_US |
dc.subject | Tuberculosis | en_US |
dc.subject | Tuberculosis, Pulmonary | en_US |
dc.title | Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development. | en_US |
dc.type | Article | en_US |
dc.rights.holder | © The Author(s) 2019 | |
dc.identifier.doi | 10.1038/s41467-019-12956-2 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/31672993 | en_US |
pubs.issue | 1 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.publisher-url | https://www.nature.com/articles/s41467-019-12956-2 | |
pubs.volume | 10 | en_US |
dcterms.dateAccepted | 2019-10-09 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |